Masatoshi Kudo1, Ann-Lii Cheng2, Joong-Won Park3, Jae Hyung Park4, Po-Chin Liang5, Hisashi Hidaka6, Namiki Izumi7, Jeong Heo8, Youn Jae Lee9, I-Shyan Sheen10, Chang-Fang Chiu11, Hitoshi Arioka12, Satoshi Morita13, Yasuaki Arai14. 1. Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan. Electronic address: m-kudo@med.kindai.ac.jp. 2. Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan. 3. Center for Liver Cancer, National Cancer Center Korea, Gyeonggi-do, South Korea. 4. Department of Radiology, Seoul National University Hospital, Seoul, South Korea; Department of Radiology, Myongji Hospital, Gyeonggi-do, South Korea. 5. Division of Abdomen Radiology, National Taiwan University Hospital, Taipei City, Taiwan. 6. Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kanagawa, Japan. 7. Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan. 8. Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, South Korea. 9. Division of Gastroenterology, Inje University Busan Paik Hospital, Busan, South Korea. 10. Department of Hepato-gastroenterology, Chang Gung Memorial Hospital-Linkou, Taoyuan County, Taiwan. 11. Division of Hematology/Oncology, China Medical University Hospital, Taichung City, Taiwan. 12. Department of Medical Oncology, Yokohama Rosai Hospital, Kanagawa, Japan. 13. Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan. 14. Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan.
Abstract
BACKGROUND:Orantinib is an oral multi-kinase inhibitor. This study was done to evaluate the efficacy of orantinib combined with conventional transcatheter arterial chemoembolisation (cTACE) in patients with unresectable hepatocellular carcinoma. METHODS: This randomised, double-blind, placebo-controlled, phase 3 study was done at 75 sites in Japan, South Korea, and Taiwan. Patients with unresectable hepatocellular carcinoma, no extra-hepatic tumour spread, and Child-Pugh score of 6 or less were randomly assigned (1:1) byinteractive web response system using a computer-generated sequence to receive orantinib or placebo, within 28 days of cTACE. Randomisation was stratified by region, Child-Pugh score (5 vs 6), alpha fetoprotein concentrations (<400 ng/mL vs ≥400 ng/mL), and size of the largest lesion (≤50 mm vs >50 mm). Orantinib at 200 mg, twice per day, or placebo was given orally until TACE failure or unacceptable toxicity. The patients, investigators, and study personnel were masked to treatment assignment. The primary endpoint was overall survival, analysed in the full analysis set (patients who had received at least one dose of study drug). This study is registered at ClinicalTrials.gov, number NCT01465464, and has been terminated. FINDINGS:Between Dec 10, 2010, and Nov 21, 2013, 889 patients were randomly assigned to receive either orantinib (445 patients; 444 treated) or placebo (444 patients; all treated). The study was ended at interim analysis for futility evaluation. Median follow-up was 17·3 months (IQR 11·3-26·4). There was no improvement in overall survival with orantinib compared with placebo (median 31·1 months [95% CI 26·5-34·5] vs 32·3 months [28·4-not reached]; hazard ratio 1·090, 95% CI 0·878-1·352; p=0·435). The main adverse events in the orantinib group were oedema, ascites, and elevation of aspartate and alanine aminotransferases. The most frequent adverse events of grade 3 or worse in the orantinib group included elevated aspartate aminotransferase (189 [43%] patients in the oratinib group, 161 [36%] patients in the placebo group), elevated alanine aminotransferase (150 [34%] patients in the oratinib group, 132 (30%) patients in the placebo group), and hypertension (47 [11%] patients in the oratinib group, 39 [9%] patients in the placebo group). Serious adverse events were reported in 200 (45%) patients in the orantinib group and 134 (30%) patients in the placebo group. INTERPRETATION:Orantinib combined with cTACE did not improve overall survival in patients with unresectable hepatocellular carcinoma. FUNDING: Taiho Pharmaceutical.
RCT Entities:
BACKGROUND:Orantinib is an oral multi-kinase inhibitor. This study was done to evaluate the efficacy of orantinib combined with conventional transcatheter arterial chemoembolisation (cTACE) in patients with unresectable hepatocellular carcinoma. METHODS: This randomised, double-blind, placebo-controlled, phase 3 study was done at 75 sites in Japan, South Korea, and Taiwan. Patients with unresectable hepatocellular carcinoma, no extra-hepatic tumour spread, and Child-Pugh score of 6 or less were randomly assigned (1:1) by interactive web response system using a computer-generated sequence to receive orantinib or placebo, within 28 days of cTACE. Randomisation was stratified by region, Child-Pugh score (5 vs 6), alpha fetoprotein concentrations (<400 ng/mL vs ≥400 ng/mL), and size of the largest lesion (≤50 mm vs >50 mm). Orantinib at 200 mg, twice per day, or placebo was given orally until TACE failure or unacceptable toxicity. The patients, investigators, and study personnel were masked to treatment assignment. The primary endpoint was overall survival, analysed in the full analysis set (patients who had received at least one dose of study drug). This study is registered at ClinicalTrials.gov, number NCT01465464, and has been terminated. FINDINGS: Between Dec 10, 2010, and Nov 21, 2013, 889 patients were randomly assigned to receive either orantinib (445 patients; 444 treated) or placebo (444 patients; all treated). The study was ended at interim analysis for futility evaluation. Median follow-up was 17·3 months (IQR 11·3-26·4). There was no improvement in overall survival with orantinib compared with placebo (median 31·1 months [95% CI 26·5-34·5] vs 32·3 months [28·4-not reached]; hazard ratio 1·090, 95% CI 0·878-1·352; p=0·435). The main adverse events in the orantinib group were oedema, ascites, and elevation of aspartate and alanine aminotransferases. The most frequent adverse events of grade 3 or worse in the orantinib group included elevated aspartate aminotransferase (189 [43%] patients in the oratinib group, 161 [36%] patients in the placebo group), elevated alanine aminotransferase (150 [34%] patients in the oratinib group, 132 (30%) patients in the placebo group), and hypertension (47 [11%] patients in the oratinib group, 39 [9%] patients in the placebo group). Serious adverse events were reported in 200 (45%) patients in the orantinib group and 134 (30%) patients in the placebo group. INTERPRETATION:Orantinib combined with cTACE did not improve overall survival in patients with unresectable hepatocellular carcinoma. FUNDING: Taiho Pharmaceutical.
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